Cytomegalovirus (CMV) is a double-stranded DNA virus in the Herpesvirus family that can cause disseminated or localized end-organ disease among patients with advanced immunosuppression. Most clinical disease occurs in previously infected (seropositive) persons and so represents either reactivation of latent infection or reinfection with a novel strain.

The diagnosis of CMV retinitis is usually made based on recognition of characteristic retinal changes observed through a dilated pupil during an ophthalmoscopic examination performed by an experienced ophthalmologist. Diagnosis by such clinical examination has a 95% positive predictive value. In rare cases, diagnosis might be difficult and PCR of vitreous for CMV and other pathogens might be valuable in the differential diagnosis.

HIV-infected persons who belong to groups at risk with relatively low seroprevalence rates for CMV and who, therefore, cannot be presumed to be seropositive should be tested for antibody to CMV (BIII). These groups include patients who have not had contact with MSM or used injection drugs. HIV-infected adolescents and adults should be advised that CMV is shed in semen, cervical secretions, and saliva and that latex condoms must always be used during sexual contact to reduce the risk for exposure to CMV and to other sexually transmitted pathogens (AII).

HIV-infected adults and adolescents who provide child care or parents of children in day care facilities should be informed that they are at increased risk for acquiring CMV infection (BI). Similarly, parents and other caretakers of HIV-infected children should be advised of the increased risk to children at these centers (BIII). Risk for acquiring CMV infection can be diminished by optimal hygienic practices (e.g., hand-washing and use of latex gloves) (AII).

HIV-exposed infants and infected children, adolescents, and adults who are seronegative for CMV and who require blood transfusion should be administered only CMV antibody-negative or leukocyte-reduced cellular blood products in nonemergency situations (BIII).

Preventing Disease

CMV end-organ disease is best prevented using ART to maintain the CD4+ count >100 cells/µL. Although oral valganciclovir would likely prevent the occurrence of CMV retinititis in patients with CD4+ counts <50 cells/µL, such therapy is not usually recommended because of cost, the potential to induce CMV resistance, the utility of treating disease when it occurs, and the lack of demonstrated survival advantage (DI). The primary method for preventing severe CMV disease is recognizing the early manifestations of the disease. Patients should be made aware of the importance of increased floaters in the eye and should be advised to assess their visual acuity regularly by using simple techniques (e.g., reading newsprint) (BIII). Regular funduscopic examinations performed by an ophthalmologist are recommended by certain
specialists for patients with low (e.g., <50 cells/µL) CD4+ counts (CIII).

For patients who have colitis or esophagitis, a majority of HIV specialists would recommend IV ganciclovir or foscarnet (or with oral valganciclovir if symptoms are not severe enough to interfere with oral absorption) for 21-28 days or until signs and symptoms have resolved (BII). Certain HIV specialists also would withhold therapy unless moderate-to-severe symptoms justify the use of systemic treatment if ART is to be initiated soon or can be optimized (BIII).

Criteria for establishing that CMV is the cause of pneumonitis and pulmonary dysfunction have been difficult to establish. If CMV is considered the cause of pulmonary dysfunction based on histology or cytology, treatment with IV ganciclovir, foscarnet, or cidofovir is logical, although few data establish that such therapy affects outcome (CIII).

For neurological disease, initiating therapy promptly is critical for an optimal clinical response. Although combination treatment with ganciclovir and foscarnet might be preferred as initial therapy to stabilize disease and maximize response (BII), this approach is associated with substantial rates of adverse effects, and optimal treatment for neurologic disease if ART can be optimized has not been established.

No data are available to demonstrate that starting ART among treatment-naïve patients with CMV retinitis would have an adverse effect on retinitis, gastrointestinal disease, or pneumonitis. Therefore, initiation of appropriate ART should be administered to those with acute CMV retinitis, gastrointestinal disease, or pneumonitis (BIII). Although no data indicate that IRIS worsens CMV neurologic disease syndromes, because of the localized morbidity that might occur with such an inflammatory reaction, a delay in initiating ART in this setting until clinical improvement occurs might be prudent (CIII).

Indirect ophthalmoscopy through a dilated pupil should be performed at the time of diagnosis of CMV retinitis, after completion of induction therapy, 1 month after the initiation of therapy, and monthly thereafter while the patient is on anti-CMV treatment (AIII). Monthly fundus photographs, using a standardized photographic technique that documents the appearance of the retina, provide the optimum method for following patients and detecting early relapse (AIII). For patients who have experienced immune recovery, the frequency of ophthalmologic follow-up can be decreased to every 3 months (AIII). Because relapse of retinitis might still occur among some patients with immune recovery, ophthalmologic follow-up might be indicated; however, the optimal timing and interval of such follow-up has not
been established.

Adverse effects of ganciclovir include neutropenia, thrombocytopenia, nausea, diarrhea, and renal dysfunction. Adverse effects of foscarnet include anemia, nephrotoxicity, and electrolyte abnormalities. For patients receiving ganciclovir or foscarnet, monitoring of complete blood counts and serum electrolytes and renal function should be performed twice weekly during induction therapy and once weekly thereafter (AIII). Cidofovir is associated with dose-related nephrotoxicity and hypotony. For patients receiving IV cidofovir, blood urea nitrogen, creatinine, and urinalysis should be performed before each infusion; administration of the drug is contraindicated if renal dysfunction or proteinuria is detected. Even in the absence of retinitis with other CMV end-organ disease, periodic ophthalmologic examinations are needed to monitor for cidofovir-associated uveitis when this agent is used.

Patients with low-level ganciclovir-resistant isolates in the eye might respond to a ganciclovir implant because of the higher local levels of ganciclovir resulting from this form of therapy. However, patients with high-level ganciclovir-resistant isolates typically will not respond and will require a switch to alternative therapy.

Repetitive intravitreous injections of ganciclovir, foscarnet, and cidofovir have been effective for secondary prophylaxis of CMV retinitis in uncontrolled case series. Because of the risk for hypotony and uveitis, the intravitreal administration of cidofovir should be reserved for extraordinary cases. Intraocular therapy alone does not provide protection to the contralateral eye or to other organ systems and typically should be combined with oral valganciclovir.

The choice of a chronic maintenance regimen for patients treated for CMV disease should be made in consultation with a specialist. For patients with retinitis, this decision should be made in consultation with an ophthalmologist and should consider the anatomic location of the retinal lesion, vision in the contralateral eye, the immunologic and virologic status of the patient, and the patient's response to ART.

Chronic maintenance therapy is not routinely recommended for gastrointestinal disease but should be considered if relapses occur (BII). A role for maintenance therapy for CMV pneumonitis has not been established (CIII).

The diagnostic considerations among pregnant women are the same as for nonpregnant women. Indications for treatment of CMV infection during pregnancy are the same as for nonpregnant HIV-infected adults (AIII). For retinal disease, use of intraocular implants or intravitreous injections for local therapy should be considered in the first trimester, if possible, to limit fetal exposure to systemically administered antiviral drugs (CIII). Systemic antiviral therapy as discussed should then be started after the first trimester.

On the basis of limited data, toxicity reports and studies, and ease of use of the various drugs, valganciclovir is recognized as the treatment of choice during pregnancy (BIII). No experience has been reported with the use of valganciclovir in human pregnancy, but concerns are expected to be the same as with ganciclovir. The fetus should be monitored by fetal-movement counting in the third trimester and by periodic ultrasound monitoring after 20 weeks of gestation to look for evidence of hydrops fetalis indicating substantial anemia. Because toxicity of foscarnet is primarily renal, weekly monitoring of amniotic fluid volumes by ultrasound is recommended after 20 weeks of gestation to detect oligohydramnios if foscarnet is used.

Cidofovir 5 mg/kg/week IV for 2 weeks, then 5 mg/kg every other week with saline hydration before and after therapy and probenecid 2 g PO 3 hours before the dose followed by 1 g PO 2 hours after the dose, and 1 g PO 8 hours after the dose (total of 4 g) (AI) Note: This regimen should be avoided in patients with sulfa allergy because of cross hypersensitivity with probenecid

The choice of initial therapy for CMV retinitis should be individualized, based on location and severity of the lesion(s), level of immunosuppression, and other factors such as concomitant medications and ability to adhere to treatment (AIII)

Initial therapy in patients with CMV retinitis, esophagitis, colitis, and pneumonitis should include initiation or optimization of ART (BIII)

In patients with CMV neurological disease, localized morbidity might occur because of IRIS, a brief delay in initiation of ART until clinical improvement might be prudent (CIII)

Maintenance therapy for CMV retinitis can be safely discontinued in patients with inactive disease and sustained CD4+ count (>100 cells/mm3 for ≥3-6 months); consultation with ophthalmologist is advised (BII)

Patients with CMV retinitis who discontinued maintenance therapy should undergo regular eye examination, optimally every 3 months, for early detection of relapse or immune recovery uveitis (IRU) (AIII) IRU might develop in the setting of immune reconstitution. Treatment of IRU: periocular corticosteroid or short courses of systemic steroid

Preferred therapy for CMV esophagitis or colitis

Ganciclovir IV or foscarnet IV for 21-28 days or until resolution of signs and symptoms (BII)

Oral valganciclovir may be used if symptoms are not severe enough to interfere with oral absorption (BII)

Maintenance therapy is usually not necessary, but should be considered after relapses (BII)

Preferred therapy CMV pneumonitis

Treatment should be considered in patients with histologic evidence of CMV pneumonitis and who do not respond to treatment of other pathogens (AIII)